New adeno-associated virus (AAV) strains isolated from animal tissues and adenoviral stocks have expanded the panel of AAV vectors available for therapeutic gene transfer applications. Comprehensive efforts to map tissue tropisms of these AAV isolates in animal models are currently underway. For instance, recent studies with AAV serotypes 1-9 indicate a broad tissue tropism in mice following intravenous administration. The AAV serotypes 8 and 9 are particularly notable for their ability to transduce multiple organs including heart, liver and skeletal muscle following intravenous administration. While the latter serotypes are well-suited for systemic gene transfer modalities, the ability to direct homing of AAV vectors to selective organs is useful for gene therapy. The development of tissue-specific promoters and miRNA-based gene regulation strategies to sharply segregate gene expression patterns among different tissue types is noteworthy in this regard. However, such regulatory components do not preclude sequestration of AAV vector genomes in off-target organs following systemic administration.
A particularly striking aspect of tissue tropisms displayed by AAV serotypes and variants is their propensity to ubiquitously accumulate within and transduce the liver, albeit with varying efficiency. The molecular basis of this preferential liver tropism has been mapped, in the case of AAV2 and AAV6, to a continuous basic footprint that appears to be involved in the interaction of either serotype with heparin. Specifically, it has previously been demonstrated that a single lysine residue on AAV6 (K531) dictates heparin binding ability and consequently, liver tropism. In corollary, substitutional mutagenesis of the corresponding glutamate/aspartate residue on other serotypes with a lysine residue confers heparin binding, possibly by forming a minimum continuous basic footprint on the capsid surface.
The present inventor addresses a need in the art for nucleic acid delivery vectors with desirable features.